A cell-adaptive nanostructured hydrogel enables an early regenerative microenvironment for peripheral nerve repair

Nerve conduits serve as critical clinical tools for peripheral nerve repair, yet delayed intraluminal endogenous cellular occupation significantly impedes early nerve regeneration. Cell-adaptive fillers capable of dynamically supporting endogenous cellular activities would provide an early regenerative microenvironment to accelerate nerve repair. Here, we show a cell-adaptive nanostructured hydrogel-filled nerve conduit for improving peripheral nerve repair. This hydrogel is formed by gelatin methacryloyl via self-assembly and photopolymerization-based printing. It features a unique nanostructure that could fast adapt cells via squeeze-induced space release. Meanwhile, this nanostructured hydrogel can promote Schwann cell proliferation and migration, and cellular contact formation, which may be associated with enhanced cell-matrix interactions and mechanotransduction-related responses. Filling into a conduit composed of inner electrospun fiber layer and outer hydrogel layer, this hydrogel significantly facilitates Schwann cell occupation compared to hollow conduits at one-week post-implantation. A 10 mm nerve defect is reconnected by regenerative nerve bridges in the hydrogel-filled conduit accompanied by substantial hydrogel degradation within 24 days. At 12 weeks post-surgery, this conduit treatment induces better nerve regeneration and functional recovery than the conventional conduit treatment. This work demonstrates a nanostructured cell-adaptive hydrogel for engineering early regenerative microenvironments, providing a promising biomaterial platform for peripheral nerve repair.